title: Essential role of SIRT1 signaling in the nucleus accumbens in cocaine and morphine action.
abstract: Sirtuins (SIRTs), class III histone deacetylases, are well characterized for their control of cellular physiology in peripheral tissues, but their influence in brain under normal and pathological conditions remains poorly understood. Here, we establish an essential role for SIRT1 and SIRT2 in regulating behavioral responses to cocaine and morphine through actions in the nucleus accumbens (NAc), a key brain reward region. We show that chronic cocaine administration increases SIRT1 and SIRT2 expression in the mouse NAc, while chronic morphine administration induces SIRT1 expression alone, with no regulation of all other sirtuin family members observed. Drug induction of SIRT1 and SIRT2 is mediated in part at the transcriptional level via the drug-induced transcription factor ΔFosB and is associated with robust histone modifications at the Sirt1 and Sirt2 genes. Viral-mediated overexpression of SIRT1 or SIRT2 in the NAc enhances the rewarding effects of both cocaine and morphine. In contrast, the local knockdown of SIRT1 from the NAc of floxed Sirt1 mice decreases drug reward. Such behavioral effects of SIRT1 occur in concert with its regulation of numerous synaptic proteins in NAc as well as with SIRT1-mediated induction of dendritic spines on NAc medium spiny neurons. These studies establish sirtuins as key mediators of the molecular and cellular plasticity induced by drugs of abuse in NAc, and of the associated behavioral adaptations, and point toward novel signaling pathways involved in drug action.
authors.affiliation: Fishberg Department of Neuroscience and Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, New York 10029, Department of Psychiatry, University of Texas Southwestern Medical Center, Dallas, Texas 78229, Department of Brain and Cognitive Sciences, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, and Laboratory of Muscle Stem Cells and Gene Regulation, National Institute of Arthritis and Musculoskeletal and Skin Diseases, Bethesda, Maryland 20892.
authors.forename: Deveroux
authors.initials: D
authors.lastname: Ferguson
authors.forename: Ja Wook
authors.initials: JW
authors.lastname: Koo
authors.forename: Jian
authors.initials: J
authors.lastname: Feng
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Heller
authors.forename: Jacqui
authors.initials: J
authors.lastname: Rabkin
authors.forename: Mitra
authors.initials: M
authors.lastname: Heshmati
authors.forename: William
authors.initials: W
authors.lastname: Renthal
authors.forename: Rachael
authors.initials: R
authors.lastname: Neve
authors.forename: Xiaochuan
authors.initials: X
authors.lastname: Liu
authors.forename: Ningyi
authors.initials: N
authors.lastname: Shao
authors.forename: Vittorio
authors.initials: V
authors.lastname: Sartorelli
authors.forename: Li
authors.initials: L
authors.lastname: Shen
authors.forename: Eric J
authors.initials: EJ
authors.lastname: Nestler
mesh_terms: D000818:Animals; D047369:Chromatin Immunoprecipitation; D003042:Cocaine / Q000494:pharmacology; D019970:Cocaine-Related Disorders / Q000378:metabolism*; D018765:Dopamine Uptake Inhibitors / Q000494:pharmacology; D015151:Immunoblotting; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009020:Morphine / Q000494:pharmacology; D009021:Morphine Dependence / Q000378:metabolism*; D009294:Narcotics / Q000494:pharmacology; D009714:Nucleus Accumbens / Q000187:drug effects / Q000378:metabolism*; D020411:Oligonucleotide Array Sequence Analysis; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012201:Reward; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology*; D056564:Sirtuin 1 / Q000378:metabolism*; D056565:Sirtuin 2 / Q000378:metabolism
chemical_list: D018765:Dopamine Uptake Inhibitors; D009294:Narcotics; D009020:Morphine; C470545:Sirt1 protein, mouse; C418743:Sirt2 protein, mouse; D056564:Sirtuin 1; D056565:Sirtuin 2; D003042:Cocaine